View source for DMMDA

{{Short description|Psychedelic drug}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 414403427
| image = DMMDA.svg
| width = 200px
| image2 = DMMDA-3d-sticks.png
| width2 = 200px

<!--Clinical data-->
| tradename =  
| pregnancy_category =  
| routes_of_administration = [[Oral administration|Oral]]

<!--Legal status-->
| legal_CA = Schedule I
| legal_UK = Class A
| legal_status =  

<!--Pharmacokinetic data-->
| bioavailability =  
| protein_bound =  
| metabolism =  
| elimination_half-life =  
| excretion =

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 15183-13-8
| UNII = Y6T4R5Z3VU
| ATC_prefix = None 
| ATC_suffix =  
| PubChem =  44349928
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 21106291
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 126311
| synonyms = 2,5-Dimethoxy-3,4-methylenedioxyamphetamine; DMMDA-1

<!--Chemical data-->
| IUPAC_name = 1-(4,7-Dimethoxy-1,3-benzodioxol-5-yl)propan-2-amine
| C=12 | H=17 | N=1 | O=4
| SMILES = CC(N)Cc1cc(OC)c2OCOc2c1OC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C12H17NO4/c1-7(13)4-8-5-9(14-2)11-12(10(8)15-3)17-6-16-11/h5,7H,4,6,13H2,1-3H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = GRGRGLVMGTVCNZ-UHFFFAOYSA-N
}}

'''2,5-Dimethoxy-3,4-methylenedioxyamphetamine''' ('''DMMDA''' or '''DMMDA-1''') is a lesser-known [[psychedelic drug]] of the [[substituted amphetamine|amphetamine]] family related to [[MMDA (drug)|MMDA]].<ref name="isbn0-9630096-0-5">{{cite book | vauthors = Shulgin A, Shulgin A | title = Pihkal: A Chemical Love Story | publisher = Transform Press | year = 1991 | isbn = 0-9630096-0-5 | url = http://www.erowid.org/library/books_online/pihkal/pihkal058.shtml}}</ref> It was first [[chemical synthesis|synthesized]] by [[Alexander Shulgin]] in the 1960s and was described in his 1991 book ''[[PiHKAL]]''.<ref name="isbn0-9630096-0-5" />

==Use and effects==
Shulgin listed the [[dose (biochemistry)|dosage]] of DMMDA in ''PiHKAL'' as 30 to 75{{nbsp}}mg and the [[duration of action|duration]] as 6 to 8{{nbsp}}hours.<ref name="isbn0-9630096-0-5" /> He reported DMMDA as producing [[LSD]]-like subjective effects: [[mental imagery|image]]s, [[mydriasis]], [[ataxia]], and [[time dilation]].<ref name="isbn0-9630096-0-5" /> DMMDA is not mentioned much in literature outside ''PiHKAL''.<ref name="isbn0-9630096-0-5" />

== Pharmacology == 
The [[mechanism of action|mechanism]] behind the subjective effects of DMMDA has not been specifically established. In ''PiHKAL'', Shulgin asserts that the subjective effects of 75{{nbsp}}mg of DMMDA are equivalent to those of 75 to 100{{nbsp}}μg of [[LSD]].<ref name="isbn0-9630096-0-5" /> LSD is a well-known [[partial agonist]] of the [[serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub>]] receptor. This may suggest that DMMDA is also an [[agonist]] or partial agonist of the 5-HT<sub>2A</sub> receptor.{{Citation needed|date=April 2025}}

DMMDA is equivalent to 12 "mescaline units" in terms of [[potency (pharmacology)|potency]]. DMMDA's isomer DMMDA-2 is equivalent to 5 "mescaline units" in terms of potency.<ref>{{Cite journal | author = Clare, Brian W. | year = 1990 | title = Structure-Activity Correlations for Psychotomimetics. 1. Phenylalkylamines: Electronic, Volume, and Hydrophobicity Parameters | journal = Journal of Medicinal Chemistry | volume = 33 | issue = 7 | pages = 687–702 | doi = 10.1021/jm00164a036 | pmid = 2299636 | url = https://www.erowid.org/archive/rhodium/pdf/sar.psychotomimetics-1.pdf | access-date = 2025-01-07}}</ref>

Repeated administration of [[mescaline]] (3,4,5-trimethoxyphenethylamine), a somewhat similar compound to DMMDA, has shown to slowly create [[drug tolerance|tolerance]]. This may suggest that the same applies to DMMDA.<ref name="mescaline">{{cite journal | vauthors = Kovacic P, Somanathan R | title = Novel, unifying mechanism for mescaline in the central nervous system: electrochemistry, catechol redox metabolite, receptor, cell signaling and structure activity relationships | journal = Oxidative Medicine and Cellular Longevity | volume = 2 | issue = 4 | pages = 181–190 | date = September 2009 | pmid = 20716904 | pmc = 2763256 | doi = 10.4161/oxim.2.4.9380 | publisher = Wiley }} {{Creative Commons text attribution notice|cc= by4 |url=|authors=|vrt=|from this source=}}</ref>

== Computationally predicted toxicology and metabolism ==
Computational prediction with ProTox-3.0 predicts that DMMDA has the following toxicological properties from most probable to least probable: respiratorically toxic (P=0.76), [[nephrotoxicity|nephrotoxic]] (P=0.58), [[ecotoxicity|ecotoxic]] (P=0.54), and [[carcinogen|carcinogenic]] (P=0.51). DMMDA is also predicted to cross the [[blood–brain barrier]] (BBB) (P=0.80).<ref name="protox">{{cite journal | vauthors = Banerjee P, Kemmler E, Dunkel M, Preissner R | title = ProTox 3.0: a webserver for the prediction of toxicity of chemicals | journal = Nucleic Acids Research | volume = 52 | issue = W1 | pages = W513–W520 | date = July 2024 | pmid = 38647086 | pmc = 11223834 | doi = 10.1093/nar/gkae303 }}</ref>

: [[File:Protox30.png|350px|thumb|left|upright=1.2|ProTox-3.0's predictions about DMMDA's toxicological properties.]]

{{Clear-left}}

DMMDA is predicted to be [[metabolism|metabolized]] via cytochrome [[CYP3A4]] (P=0.60).<ref name="protox" /> DMMDA is somewhat similar to [[MDMA|3,4-methylenedioxy-1-N,α-dimethylphenylethylamine]] which is primarily metabolized into 3,4-dihydroxy-1-N,α-dimethylphenylethylamine. This may suggest that DMMDA can be metabolized into 3,4-dihydroxy-2,5-dimethoxy-1-α-methylphenylethylamine. The metabolism of [[mescaline|3,4,5-trimethoxyphenylethylamine]] results in the demethylation of its methoxy groups, which may suggest that metabolism of DMMDA may also result in the demethylation of its methoxy groups.<ref>{{cite journal | doi=10.1124/jpet.111.180612 | title=Metabolism and Disposition of 3,4-Methylenedioxymethamphetamine ("Ecstasy") in Baboons after Oral Administration: Comparison with Humans Reveals Marked Differences | date=2011 | journal=The Journal of Pharmacology and Experimental Therapeutics | volume=338 | issue=1 | pages=310–317 | pmid=21493752 | pmc=3126644 | vauthors = Mueller M, Goodwin AK, Ator NA, McCann UD, Ricaurte GA }}</ref><ref name="mescaline" />

== Chemistry ==
[[File:Pseudodillapiolesynthesis.png|350px|thumb|right|upright=1.2|Precursors in the synthesis of DMMDA and its regioisomers.]]

Shulgin explains in his book that DMMDA has 6 isomers similar to [[Trimethoxyamphetamine|TMA]].<ref name="isbn0-9630096-0-5" /> [[DMMDA-2]] is the only other isomer that has been synthesized as of yet. DMMDA-3 could be made from [[exalatacin]] (1-allyl-2,6-dimethoxy-3,4-methylenedioxybenzene). Exalatacin can be found in the [[essential oil]] of both [[Crowea exalata]] and [[Crowea angustifolia]] var. angustifolia.<ref name="oil">{{cite journal | vauthors = Brophy JJ, Goldsack RJ, Punruckvong A, Forster PI, Fookes CJ | title = Essential oils of the genus Crowea (Rutaceae). | journal = Journal of Essential Oil Research | date = July 1997 | volume = 9 | issue = 4 | pages = 401–409 | doi = 10.1080/10412905.1997.9700740 }}</ref> In other words, exalatacin is an isomer of both [[apiole]] and [[dillapiole]], which can be used to make DMMDA and DMMDA-2 respectively. Additionally, yet another isomer of DMMDA could be made from pseudodillapiole or 4,5-dimethoxy-2,3-methylenedioxyallylbenzene.<ref name="patent">{{cite patent| country = US| number = 4,876,277| status = patent| title = Antimicrobial/antifungal compositions| gdate = 1989-10-24| inventor	= Burke BA, Nair MG | assign1 = Plant Cell Research Institute, Inc., Dublin, Calif. | url = https://patents.google.com/patent/US4876277A/en?oq=US4876277A}}</ref> The last two isomers of DMMDA are 5,6-dimethoxy-2,3-methylenedioxy-1-α-methylphenylethylamine and 4,6-dimethoxy-2,3-methylenedioxy-1-α-methylphenylethylamine.

Like all other α-methylphenylethylamine derivative compounds, DMMDA and its [[regioisomer]] have two [[enantiomer]]s due to the methyl group being in the alpha position of the ethyl group in position number 1 on the benzene ring.<ref>{{cite journal | vauthors = Campbell JL, Kafle A, Bowman Z, Blanc JC, Liu C, Hopkins WS | title = Separating chiral isomers of amphetamine and methamphetamine using chemical derivatization and differential mobility spectrometry | journal =  Analytical Science Advances| volume = 1 | issue = 4 | pages = 233–244 | date = December 2020 | pmid = 38716384 | doi = 10.1002/ansa.202000066 |doi-access=free | pmc = 10989161 }}</ref> There is no information regarding the differences in the pharmacological effects of (S)-DMMDA and (R)-DMMDA.

=== Shulgin's synthesis ===
Shulgin describes the synthesis of DMMDA from [[apiole]] in his ''PiHKAL''.<ref name="isbn0-9630096-0-5" /> Apiole is subjected to an [[isomerization reaction]] to yield [[isoapiole]] by adding to solution of ethanolic [[potassium hydroxide]] and holding the solution at a steam bath.<ref name="isbn0-9630096-0-5" /> Isoapiole is then [[nitration|nitrated]] via a [[Knoevenagel condensation]] to 2-nitro-isoapiole or 1-(2,3-dimethoxy-3,4-methylenedioxyphenyl)-2-nitropropene by adding it to a stirred solution of [[acetone]] and [[pyridine]] at ice-bath temperatures and treating the solution with [[tetranitromethane]]. The [[pyridine]] acts as a catalyst in this reaction.<ref name="isbn0-9630096-0-5" /> 2,5-dimethoxy-3,4-methylenedioxybenzaldehyde can also be used as precursors in this step of the synthesis. The 2-nitro-isoapiole is finally [[Reduction_of_nitro_compounds#Reduction_to_amines|reduced]] to [[free base|freebase]] DMMDA by adding it to a well-stirred and [[reflux|refluxing]] suspension of [[diethylether]] and [[lithium aluminium hydride]] under an inert atmosphere.<ref name="isbn0-9630096-0-5" /> The reduction can also be achieved with pressurized hydrogen. Finally, the freebase DMMDA converted into its [[hydrochloride]] salt.<ref name="isbn0-9630096-0-5" />

: [[File:2-nitro-isoapiole.png|600px|thumb|left|upright=1.2|Alexander Shulgin's synthesis of DMMDA.]]

{{Clear-left}}

=== Other synthetic methods ===
Shulgin's synthesis of DMMDA can reasonably be considered unsafe, at least by modern standards, since it uses [[tetranitromethane]] for its nitration reaction, which is toxic, carcinogenic and prone to detonating.<ref>{{ Cite web | url = https://ntp.niehs.nih.gov/ntp/roc/content/profiles/tetranitromethane.pdf | work = Report On Carcinogens | edition = 12th | year = 2011 | title = Tetranitromethane | access-date = 2012-08-14 | author = National Toxicology Program | publisher = [[National Toxicology Program]] | url-status = live | archive-url = https://web.archive.org/web/20130131171438/http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Tetranitromethane.pdf | archive-date = 2013-01-31 | author-link = National Toxicology Program }}</ref> DMMDA can be made from apiole via other safer methods. Among other methods, DMMDA can be synthesized from apiole via the intermediate chemical 2,5-dimethoxy-3,4-methylenedioxyphenylpropan-2-one or DMMDP2P in the same manner as [[3,4-Methylenedioxyamphetamine|MDA]] is made from [[safrole]].

DMMDP2P can be made from apiole via a [[Wacker oxidation]] with [[benzoquinone]]. DMMDP2P can be alternatively made by subjecting apiole to an [[isomerisation]] reaction to yield the thermodynamically stabler internal alkene, isoapiole, followed by a peroxyacid [[Baeyer-Villiger oxidation|oxidation]], with for example peracetic acid, and finally a [[hydrolysis |hydrolytic]] [[dehydration]].<ref name="Cox_2008">{{cite journal | vauthors = Cox M, Klass G, Morey S, Pigou P | title = Chemical markers from the peracid oxidation of isosafrole | journal = Forensic Science International | volume = 179 | issue = 1 | pages = 44–53 | date = July 2008 | pmid = 18508215 | doi = 10.1016/j.forsciint.2008.04.009 }}</ref> Peroxyacids can be made by combining hydrogen peroxide with an acid like formic acid or acetic acid to create performic acid or peracetic acid. It has been suggested that peroxynitric acid could also be used in this synthesis.<ref>{{cite web | vauthors = Morris H |title=This Chemist Made 200KG of MDA a WEEK |url=https://www.youtube.com/watch?v=exampleurl |website=YouTube |date=2022-12-25 |access-date=2024-12-13}}</ref> The oxidation first creates an epoxide in the alkene of isoapiole and then isopaiole glycol's monoformate ester if peracetic acid is used.<ref name="Waumans_2004">{{cite journal | vauthors = Waumans D, Hermans B, Bruneel N, Tytgat J | title = A neolignan-type impurity arising from the peracid oxidation reaction of anethole in the surreptitious synthesis of 4-methoxyamphetamine (PMA) | journal = Forensic Science International | volume = 143 | issue = 2–3 | pages = 133–9 | date = July 2004 | pmid = 15240033 | doi = 10.1016/j.forsciint.2004.02.033 }}</ref> The hydrolysis is usually acid-catalyzed with a strong acid, such as sulphuric acid or hydrochloric acid, because the strong acid will also result in the intermediary isoapiole monoformyl glycol being dehydrated to DMMDP2P via a pinacol rearrangement. A small amount of the epoxide can form a carboxycation, which can rearrange itself to DMMDP2P, or react with water to form isoapiole glycol. Thus only one reagent, sulphuric acid, is needed for both the hydrolysis and dehydration and both reactions can be done in the same reaction vessel. Then the DMMDP2P can then be subjected to a [[reductive amination]] with a source of [[nitrogen]], such as [[ammonium chloride]] or [[ammonium nitrate]], and a reducing agent, such as [[sodium cyanoborohydride]], an [[Amalgam (chemistry)|amalgam]] of [[Mercury (element)|mercury]] and [[aluminium]] or pressurized hydrogen, to yield freebase DMMDA.<ref name="Braun_1980">{{cite journal | vauthors = Braun U, Shulgin AT, Braun G | title = Centrally active N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (3,4-methylenedioxyamphetamine) | journal = Journal of Pharmaceutical Sciences | volume = 69 | issue = 2 | pages = 192–195 | date = February 1980 | pmid = 6102141 | doi = 10.1002/jps.2600690220 }}</ref><ref name="organic">{{cite book | vauthors = Clayden J, Greeves N, Warren S |title=Organic Chemistry |year=2012 |pages=234–235 |publisher=Oxford University Press |isbn=978-0-19-927029-3 |language=en}}</ref><ref name="advanced">{{cite book | vauthors = Carey FA, Sundberg RJ |title=Organic Chemistry B: Reactions and Synthesis |year=2007 |pages=403–404 |publisher=Springer |isbn=978-0-387-68350-8 |language=en}}</ref><ref name="March">{{cite book | vauthors = Smith MB, March J |title=March's Advanced Organic Chemistry |year=2007 |pages=1288–1290 |publisher=John Wiley & Sons |isbn=978-0-471-72091-1 |language=en}}</ref><ref name ="kirk-othmer">{{cite book | vauthors = Turcotte MG, Hayes KS |title=Amines, Lower Aliphatic Amines, Kirk-Othmer Encyclopedia of Chemical Technology |year=2001 |publisher=John Wiley & Sons |location=New York}}</ref>

:[[File:Modernfixed synthesis.png|600px|thumb|left|upright=1.2|Alternative synthesis of DMMDA.]]{{clear-left}}

=== General synthetic information ===
Sodium borohydride usually is not used as a reducing agent due to it being much stronger than sodium cyanoborohydride; this usually results in side products in addition to DMMDA. Reductive aminations are exothermic reactions. Thus it is necessary to employ different methods of cooling the reaction mixture to prevent overheating; this can be accomplished by using a large amount of solvent or an ice bath, for example. The use of a mercury amalgam is unsafe due to mercury's well-known toxic effects on the central nervous system. In addition to [[peracetic acid]], other [[peroxy acid]]s can be used for the peroxy acid oxidation of isoapiole and other analogues of isoallylbenzene in general. For example, combining nitric acid with hydrogen peroxide would result in the same reaction.<ref name="organic" /><ref name="advanced" /><ref name="March" /><ref name ="kirk-othmer" />

==History==
DMMDA was first described in the [[scientific literature]] by [[Alexander Shulgin]] and colleagues by 1967.<ref name="ShulginSargent1967">{{cite journal | vauthors = Shulgin AT, Sargent T | title = Psychotrophic phenylisopropylamines derived from apiole and dillapiole | journal = Nature | volume = 215 | issue = 5109 | pages = 1494–1495 | date = September 1967 | pmid = 4861200 | doi = 10.1038/2151494b0 | bibcode = 1967Natur.215.1494S | url = https://chemistry.mdma.ch/hiveboard/rhodium/dmmda.shulgin.html| url-access = subscription }}</ref><ref name="ShulginSargentNaranjo1967">{{cite journal | vauthors = Shulgin AT, Sargent T, Naranjo C | title = The chemistry and psychopharmacology of nutmeg and of several related phenylisopropylamines | journal = Psychopharmacol Bull | volume = 4 | issue = 3 | pages = 13 | date = December 1967 | pmid = 5615546 | doi = | url = https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=a15476299fba3b3a535958d0b198e813816ce768}}</ref>

==See also==
* [[Substituted methylenedioxyphenethylamine]]
* [[Substituted methoxyphenethylamine]]
* [[Dimethoxymethylenedioxyamphetamine]]
* [[Methoxymethylenedioxyamphetamine]]
* [[2,3,4,5-Tetramethoxyamphetamine]] (TeMA)

==References==
{{Reflist}}

==External links==
* [https://isomerdesign.com/pihkal/explore/58 DMMDA - Isomer Design]
* [https://www.erowid.org/library/books_online/pihkal/pihkal058.shtml DMMDA - PiHKAL - Erowid]
* [https://isomerdesign.com/pihkal/read/pk/58 DMMDA - PiHKAL - Isomer Design]

{{Psychedelics}}
{{Serotonin receptor modulators}}
{{Phenethylamines}}

[[Category:2,5-Dimethoxyphenethylamines]]
[[Category:Hydroxyquinol ethers]]
[[Category:Methylenedioxyphenethylamines]]
[[Category:Psychedelic phenethylamines]]